Citations

OBJECTIVE The aim of this study was to determine predictors of the minimum clinically important difference (MCID) in the Neck Disability Index (NDI) following cervical spinal deformity surgery. METHODS A retrospective review was performed of a prospective, multicenter adult cervical spinal deformity database. All patients had baseline and 1-year NDI scores. Patients met MCID with an improvement of NDI by 7 points between baseline and 1 year, as previously established. Baseline demographics, comorbidities, and both baseline and 1-year spinopelvic parameters were evaluated for statistical significance in a univariate logistic regression analysis. Significant variables, in addition to baseline NDI, were analyzed in a multivariable logistic regression model by backward selection with Akaike information criterion minimization. RESULTS A total of 122 patients were included with a median age of 62 (IQR 56, 69) years; 62% of patients were female. Of the 122 patients, 72 (59%) achieved NDI MCID at 1 year. Predictors of achieving MCID on univariate analysis included a lower Charlson Comorbidity Index (CCI) total score (OR 0.70, p = 0.03), depression as a comorbidity (OR 2.9, p = 0.02), lower C2 tilt at the 1-year follow-up (OR 0.92, p = 0.02), and a greater difference between 1-year postoperative C2–7 sagittal vertical axis (SVA) and preoperative C2–7 SVA (OR 0.98, p = 0.0495). On multivariable logistic regression analysis, predictors of achieving MCID included a lower CCI (OR 0.62, p = 0.03), depression as a comorbidity (OR 3.1, p = 0.059), a greater change in C2–7 SVA at the 1-year follow-up compared with baseline (OR 0.97, p = 0.055), and baseline NDI (OR 1.02, p = 0.24) with an area under the curve of 0.74. CONCLUSIONS The best-fit multivariable model included higher baseline NDI, a greater change in C2–7 SVA, patient-reported baseline depression, and lower CCI as important factors in predicting NDI MCID.

Abstract Background Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort. Methods Lithium-heparin plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 IFCC guidance. Uniform and sex-specific 99th percentile URLs and nonparametric 95% CIs were determined in plasma and serum separately and combined. Results The final study population comprised 4147 participants (52.5% female) with a median (25th–75th percentiles) age of 48.0 (33.0–59.0) years; 45.8%, 47.9%, 5.2%, and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n = 8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16–23) ng/L for females and 32 (28–35) ng/L for males; the uniform 99th percentile URL was 27 (24–31) ng/L. URLs were comparable in plasma and serum samples. Conclusions This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used in a large, global, healthy reference population.

Abstract Background Alzheimer Disease (AD) pathology evolves over decades, and understanding this progression is critical to the understanding of the disease and timing therapeutic interventions. Since individuals with Autosomal Dominant AD (ADAD) develop symptoms around the same age as their parent, it is possible to predict symptom onset and stage individuals by their estimated years to symptom onset (EYO). This approach does not generalize to other forms of AD, thus there is a pressing need for the timecourse of ADAD to be defined in broadly relevant terms. The objective of this project is to validate the Sampled Iterative Local Approximation (SILA) algorithm in a cohort with a known disease timecourse. SILA generates an estimate of time from amyloid positivity (A time ) based on longitudinal PET data. Method We evaluated A time in a longitudinal ADAD sample ( N = 316) with PET PiB data in three ways. First, we compared predicted age at amyloid positive (A+) to observed age at A+ for individuals who became A+ during enrollment. Next, using linear regression, we compared estimated age at A+ to estimated age at symptom onset (EYO=0). Finally, we used generalized additive models to compare the amount of variance in concurrent cognitive performance explained both A time and EYO. Result We observed a mean average error of 1.15 years between actual age at A+ ( N = 26) and the SILA‐predicted A time . Across all participants, SILA‐estimated age at A+ explained 39% of the variance in estimated age at symptom onset ( β = 0.918, p < 0.0001). Finally, we observed a nonlinear association between cognition and both A time and EYO. A time explained 19% of the variance in the general cognitive composite while EYO explained 43% of the variance. Conclusion SILA produces a valid estimate of time‐from‐amyloid positivity in ADAD. This work allows for disease stage in ADAD to be compared to staging for broad forms of AD, which was not previously possible using EYO. However, this work also illustrates that there is a high degree of heterogeneity in preclinical disease duration that is not explained by amyloid alone.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Abstract BACKGROUND CNS ependymal tumors rarely demonstrate mixed subependymal and ependymal pathology. The clinical course of these tumors is difficult to predict, but prior studies have identified TERT mutations and loss of chromosome 6 as poor prognostic factors in these tumors when located in the posterior fossa. METHODS In this retrospective single-institution study, patients with a diagnosis of mixed subependymoma/ependymoma were identified and chart reviewed to describe demographics, pathological findings, treatment courses and clinical outcomes. RESULTS Eleven patients (median age 57, 2 female, 9 male) were identified. Ten tumors were in the posterior fossa and 1 in the cervical spine. At diagnosis, 2 underwent gross total resection, 8 underwent subtotal resection, and 1 was only biopsied. Radiotherapy was administered to 5 patients at initial diagnosis (54Gy in 30 fractions). Systemic therapy (temozolomide and bevacizumab) was administered at recurrence to 2 patients. Loss of chromosome 6 was present in 5 /11 patients and TERT mutations were present in 4/11 patients, with both present in 3/11 patients. Median progression-free survival (mPFS) was 90.1 months (95% CI: 90.1–NA), with 3 progression events observed at 22, 90, and 107 months. Median follow-up duration was 27.9 months. Receiving radiotherapy had a longer mPFS (98 vs 22 months, p=0.15), although non-significant. At the time of data cut-off none of the patients were deceased. CONCLUSIONS Mixed subependymoma/ependymoma is a rare diagnosis with varying clinical outcomes. Our case series demonstrated that the majority of patients did not exhibit the previously identified poor prognostic factors. Although non-significant due to limited case numbers, radiotherapy was suggestive of longer mPFS.

Abstract Pontine H3 K27-altered diffuse midline gliomas (DMGs) are rare, fatal pediatric brain tumors resistant to systemic therapies due to the blood-brain barrier (BBB) and efflux transporters (ETs), which actively clear drugs from the brain. Convection-enhanced delivery (CED) bypasses the BBB by directly infusing therapeutics into the tumor, but maintaining adequate drug concentrations remains a challenge. This study explores strategies to enhance drug-tumor residence time and improve treatment efficacy. Using chemical modeling, FDA-approved drugs identified in prior high-throughput screening efforts were classified based on physiochemical properties impacting CED pharmacokinetics, including BBB penetration and ET substrate status. Drug behavior was validated in patient-derived in vitro and in vivo DMG models. The impact of systemic drug co-administration on drug retention and therapeutic efficacy was evaluated using multiple patient-derived orthotopic xenograft (PDOX) models. ET substrate drugs exhibited rapid elimination from the brain post-CED, limiting their therapeutic potential. However, systemic everolimus administration prolonged drug retention and potentiated the effects of efflux substrate drugs delivered via CED (e.g., topotecan, ponatinib). This combinatorial approach significantly enhanced anticancer effects in multiple PDOX models, demonstrating improved tumor control compared to monotherapy. Overall, these findings suggest that pharmacological inhibition of ETs via systemic everolimus administration can enhance drug retention in DMG when combined with CED. The observed synergistic effects highlight a promising strategy to overcome drug clearance limitations and improve treatment outcomes. Further clinical investigation is warranted to validate this approach in patients.

Abstract Diffuse midline and diffuse hemispheric glioma contain the driver mutations H3.3 K27M and G34R/V, respectively. These mutations alter histone methylations, suggesting that dysregulation of gene expression may contribute to tumor formation. We recently reported that these mutations also inhibit the phosphorylation of H3.3 at Serine 31. Importantly, H3.3 S31A mice developed high-grade gliomas – similar to those from G34R and K27M mice – indicating that loss of phosphoS31 promotes gliomagenesis. Chk1, a key kinase in DNA damage response and mitotic fidelity, phosphorylates H3.3 S31. H3.3 S31 is phosphorylated at the pericentromere in metaphase and is typically absent during interphase. Reduction of S31 phosphorylation by H3.3 K27M, G34R, G34V, or S31A was sufficient to induce mitotic errors leading to aneuploidy. Using CRISPR/Cas9, we generated novel H3.3 WT/WT and WT/S31A lines from glioma patient-derived SF-8628 (H3.3 WT/K27M) and KNS-42 (H3.3 WT/G34V) cells. Immunofluorescence of metaphase spreads revealed H3.3 phosphoS31 at the pericentromeres as expected. Interestingly, total Chk1 and active Chk1 (pS296) were significantly enriched at the pericentromeres of H3.3 K27M and G34V cells, as compared to H3.3 WT cells. While total ATR and active ATR (pT1989) were present at the pericentromere, their levels were unaltered by the H3.3 mutations. Surface plasmon resonance of purified proteins revealed that Chk1 has two binding affinities for H3.3 - likely corresponding to the previously identified Chk1 phosphorylation sites (T11 and S31) on H3.3. Chk1 binding at one site was unaffected by H3.3 K27M, while the second site showed an altered dissociation from H3.3 K27M. In summary, our data suggest that the low pericentromeric pS31 levels associated with H3.3 glioma mutations result from Chk1 recognizing the mutant histone, but without completing a phosphorylation cycle, becoming trapped at the pericentromere. This result suggests that H3.3 mutations, by trapping Chk1, may impede Chk1 activities beyond just reducing H3.3 phosphorylation.

Background Immune-related adverse events (irAEs) remain largely unpredictable, potentially affecting multiple organ systems and occurring at almost any point during and even occasionally after immune checkpoint inhibitor (ICI) treatment. To identify populations at risk for these immune-mediated toxicities, we analyzed genetic characteristics and immune markers associated with clinically significant irAEs. Methods We carried out a genome-wide association study on 373 white patients receiving ICI treatment. We identified single nucleotide polymorphisms associated with irAEs. Blood cytokine profiling and peripheral blood mononuclear cell RNA sequencing were performed at pretreatment baseline and 6–8 weeks after ICI initiation. Findings were validated in two external cohorts. Results We identified genetic haplotypes in VWA8 (Von Willebrand Factor A Domain Containing 8) , OSBPL6 (Oxysterol Binding Protein Like 6), and ADAMTS9-AS2 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 Antisense RNA 2) associated with grade ≥2 irAEs. Patients carrying risk haplotypes for one or more genes exhibited significantly greater rates of grade ≥2 (OR 3.02; 95% CI 1.83 to 5.02; p<0.001), grade ≥3 (OR 3.59; 95% CI 1.93 to 6.64; p<0.001), and multiple type irAE (OR 2.60; 95% CI 1.53 to 4.39; p<0.001). Serum CCL3 levels were significantly elevated in individuals carrying risk haplotypes (p=0.03). Gene expression analysis demonstrated activated autoimmune and inflammatory pathways in the genetic risk group. Conclusions Novel polymorphisms in VWA8, OSBPL6, and ADAMTS9-AS2 may impact immune pathways, promote inflammation, potentiate autoimmune phenotypes, and convey risk of irAE in ICI-treated patients.

OBJECTIVE Neurosurgeon scientists play a unique role in advancing neuroscience research. While previous publications have explored trends in federal and foundation funding among neurosurgeons, funding is often dominated by neurosurgical oncologists and functional neurosurgeons. Less is known about the research efforts of pediatric neurosurgeons. The aim of this study was to survey the members of the American Society of Pediatric Neurosurgeons (ASPN) to provide an overview of past research experience, current involvement, funding, and research priorities among pediatric neurosurgeons, and to gather insights that could shape future efforts to advance pediatric neurosurgical research. METHODS A survey was developed using the REDCap platform and distributed to all ASPN members via email. Survey questions used branching logic and were organized into 5 sections: 1) demographics, 2) research experience during training, 3) research experience as an attending physician, 4) research priorities, and 5) multicenter consortiums. RESULTS One hundred thirty-nine respondents completed more than half of the survey, for an overall response rate of 52.1%. Most respondents (96.4%) participated in research during their training, but only 38.1% had received a grant during training. In contrast, 83.9% of respondents were actively engaged in research as an attending physician, and 48.7% reported active funding (60.7% federal, 41.8% from foundations, and 42.9% internal). Furthermore, 74.8% of respondents reported being a member of a multicenter research consortium, and 82.4% agreed that multicenter research is important. Seventy percent of respondents agreed that the ASPN should facilitate multicenter consortium-based pediatric neurosurgical research, offering free-text responses with the following suggestions: 1) set aside time at the annual meeting to discuss multicenter research (22.9%); 2) encourage collaboration and facilitate networking (42.9%); 3) provide centralized core services such as a data coordinator and biostatistician (12.9%); and 4) provide training, education, and mentoring (7.1%). CONCLUSIONS The survey provided a cross-sectional analysis of the pediatric neurosurgical research landscape, highlighting the current state of research experience, funding, and the perspectives of pediatric neurosurgeons regarding research priorities. Despite the challenges, there is clear recognition of the importance of multicenter research collaboration. These findings reinforce the ongoing necessity of organized initiatives to support pediatric neurosurgical research and offer actionable insights into how organized pediatric neurosurgery can contribute to this critical endeavor.